This research program takes advantage of a validated preclinical rat model with the long-term aim of establishing a multi-level mechanistic account of both impaired and successful cognitive aging, spanning from molecular substrates to cortical network dynamics. A key feature of this animal model is that it is optimized for documenting reliable individual differences in the cognitive outcome of aging, from aged individuals that exhibit substantial impairment to other, aged-matched subjects that score on par with young adults. Ultimately, studies in this model are aimed at defining the essential neurobiological changes that render aging the single greatest risk for Alzheimers disease. Advances from research in this model cut across multiple levels of analysis, from studies on the contribution of epigenetic regulation of gene expression, to behavioral investigations asking how aging alters the interactions between multiple memory systems in brains. The project has also enabled a range of collaborative studies with both intra- and extramural partners, including investigators at the National Institute on Drug Abuse, Johns Hopkins University, University of California Irvine, and the University of Washington. In a recently published study, for example, we aimed to examined the effects of aging on the integrity of network resting state functional connectivity (rs-FC), specifically in relation to individual differences in the cognitive outcome of aging (Ash et al., 2016). Aged rats with impaired spatial memory displayed a distinct network signature relative to both young and aged animals with normal memory, comprising a widely distributed pattern of reduced functional connectivity with a seed in the retrosplenial cortex. A related study examining the same neuroimaging dataset provided additional detail, demonstrating that within regions comprising the default mode network (DMN), changes in functional connectivity in aged rats with memory impairment were most prominent in a posterior parietal/visual cortex module of the DMN (Hsu et al., 2016). These studies also contribute to growing evidence, across multiple levels of analysis, that successful cognitive aging is supported by a distinct, neuroadaptive trajectory, not simply the endurance of a youthful condition. Complementing results from gene expression, epigenetic and behavioral studies in this model, aged animals with preserved memory exhibited a distinct pattern of connectivity with the retrosplenial cortex, prominently including the loss of an anti-correlated network seen in younger animals. Identifying strategies that engage positive neuroadaptive trajectories of cognitive aging is an important focus of current research.
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